T cell-independent eradication of experimental glioma by intravenous TLR7/8-agonist-loaded nanoparticles.

Dennis A Agardy, Michael Platten, Michael O Breckwoldt, Christopher B Rodell, Martin Bendszus, Philipp Vollmuth, Sabine Heiland, Wolfgang Wick, Ralph Weissleder, Martina U Muckenthaler, Matthias Schlesner, Theresa Bunse, Abdulrahman Alsasa, Shreya S Soni, Verena Turco, Sandro Altamura, Duy Nguyen, Yannik Streibel, Volker Sturm, Kristine Jähne, Gianluca Brugnara, Manuel Fischer, Katharina Schregel, Kianush Karimian-Jazi, Natalie K Horvat, Jessica Hunger, Kira Pfleiderer

Journal: Nature communications 2023;14(1):771

PMID: 36774352

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Abstract

Glioblastoma, the most common and aggressive primary brain tumor type, is considered an immunologically "cold" tumor with sparse infiltration by adaptive immune cells. Immunosuppressive tumor-associated myeloid cells are drivers of tumor progression. Therefore, targeting and reprogramming intratumoral myeloid cells is an appealing therapeutic strategy. Here, we investigate a β-cyclodextrin nanoparticle (CDNP) formulation encapsulating the Toll-like receptor 7 and 8 (TLR7/8) agonist R848 (CDNP-R848) to reprogram myeloid cells in the glioma microenvironment. We show that intravenous monotherapy with CDNP-R848 induces regression of established syngeneic experimental glioma, resulting in increased survival rates compared with unloaded CDNP controls. Mechanistically, CDNP-R848 treatment reshapes the immunosuppressive tumor microenvironment and orchestrates tumor clearing by pro-inflammatory tumor-associated myeloid cells, independently of T cells and NK cells. Using serial magnetic resonance imaging, we identify a radiomic signature in response to CDNP-R848 treatment and ultrasmall superparamagnetic iron oxide (USPIO) imaging reveals that immunosuppressive macrophage recruitment is reduced by CDNP-R848. In conclusion, CDNP-R848 induces tumor regression in experimental glioma by targeting blood-borne macrophages without requiring adaptive immunity.

Address: Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK) within the German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.; Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany.; Neuroradiology Department, University Hospital Heidelberg, 69120, Heidelberg, Germany.; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.; Department of Pediatric Oncology, Hematology and Immunology, University Hospital, Heidelberg, Germany.; Molecular Medicine Partnership Unit (MMPU), Heidelberg University, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.; Junior Research Group Bioinformatics and Omics Data Analytics, DKFZ, Heidelberg, Germany.; School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, 19104, USA.; Biomedical Informatics, Data Mining and Data Analytics, Faculty of Applied Computer Science and Medical Faculty, University of Augsburg, Augsburg, Germany.; Center for Systems Biology, Massachusetts General Hospital, Boston, MA, 02114, USA.; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.; Clinical Cooperation Unit Neurooncology, DKTK within DKFZ, Heidelberg, Germany.; Department of Neurology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany.; Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK) within the German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. [email protected].; Neuroradiology Department, University Hospital Heidelberg, 69120, Heidelberg, Germany. [email protected].; Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK) within the German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. [email protected].; Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neurosciences, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany. [email protected].

DOI: 10.1038/s41467-023-36321-6

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MeSH Terms: Humans, Adjuvants, Immunologic, Glioma, Macrophages, Nanoparticles, T-Lymphocytes, Toll-Like Receptor 7, Tumor Microenvironment, Toll-Like Receptor 8